Interferon protein therapy is well established in the clinical environment as a treatment for a variety of cancers. Two widely used commercially available interferon species produced by recombinant DNA technology are interferon α-2b recombinant (Intron A®, Schering Corporation) and interferon α-2a recombinant (Roferon®, Hoffman LaRoche, Inc.). Intron A is indicated for use in the treatment of malignant melanoma in combination with surgery, aggressive follicular Non-Hodgkin's Lymphoma in combination with anthracycline chemotherapy, intralesional treatment of condylomata acuminata, hairy cell leukemia, and AIDS-Related Kaposi's Sarcoma. Roferon is indicated for use in the treatment of Philadelphia chromosome positive chronic myelogenous leukemia (CML) and AIDS-related Kaposi's sarcoma.
Additionally, investigational approaches to the use of recombinant vectors encoding interferon species have been evaluated for anti-tumor effects including the treatment of cancers of the ovary, kidney, and bladder, multiple myeloma, melanoma, certain lymphomas and leukemias, and Kaposi's sarcoma. The antitumor activities of replication deficient adenoviruses encoding interferon (Ad-IFNα) have been reported against a variety of human tumor xenografts following direct injection (Ahmed et. al., Cancer Gene Therapy, 8:788-95 (2001)), which included human transitional bladder carcinoma (TCC) xenografts (Izawa et al., Clin. Cancer Res., 8:1258-1270 (2002)). These studies show that interferon can mediate both direct antitumor activity and a significant bystander effect, characterized by the activation of host effector cells, enhanced apoptosis, and the inhibition of angiogenesis.
One particularly notable application where recombinant interferon protein has been evaluated for efficacy is in the treatment of bladder cancer. Superficial bladder cancers are diagnosed in over 45,000 patients/year in the United States. The disease is typically characterized as a slowly progressing malignancy that originates from the surface lining of the urothelium. While most of these superficial cancers can be adequately managed with periodic transurethral resection (TUR) and surveillance, this is far from an optimal approach because 60 to 70 percent of superficial tumors recur after TUR, and up to 30 percent evolve into more aggressive, potentially lethal cancers. The high recurrence rate and the unpredictability of the progression patterns have led to the widespread use of intravesical therapy for local control of the disease. Immunotherapy with intravesically instilled Bacillus Calmette-Guerin (BCG) can usually delay disease progression in newly diagnosed patients. Unfortunately this therapy does not produce a qualitative change in the underlying biology of the tumor and many patients remain at substantial risk of eventual progressing to invasive, life-threatening cancer. In fact, even with close surveillance and follow-up, at least 50% of patients will eventually recur, and 30% will die of metastatic bladder cancer, despite originally presenting with “only” carcinoma in situ. Herr et al., J. Urol., 163:60-61 (2000) and Dalbagni et al., Urol. Clin. North Am., 27:137-146 (2000). Clearly, more effective intravesical therapies are necessary to improve overall survival and provide an alternative to radical cystectomy.
Intravesical interferon-α2b (IFNα2b) recombinant (Intron A) is well tolerated as a monotherapy in superficial bladder cancer patients and is an approved indication for this agent in many countries. Intron A has demonstrated dose-related clinical efficacy as a salvage therapy in the scenario of BCG failure, although the durability of the response is limited and most patients relapse within the first year of treatment. Belldegrun et al., J. Urol., 159(6):1793-801 (1998). Recently, Intron A has been combined with BCG in an attempt to enhance the cellular immune response to BCG and improve the response to therapy. O'Donnell et al., J. Urol., 166:1300-1304 (2001). Combination therapy has been effective in BCG refractory TCC, but many of these initial responders relapse with superficial disease and ultimately require cystectomy.
Gene therapy employing recombinant vectors encoding interferon species provides a promising alternate approach to the treatment of refractory superficial bladder cancer. Local delivery can maximize transgene expression in the urothelium and minimize vector distribution to vital organs outside of the bladder. In addition, efficient transfer of a gene encoding a secreted protein (e.g., IFNα2b) to both normal and malignant cells of the urothelium can generate a potent anti-tumor bystander effect coincident with sustained local protein concentrations in the urine.